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Page 8 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

Although several rational attempts have been made to improve the R-CHOP backbone [23,39-49] , with a
particular emphasis on ABC/non-GC-DLBCL subtype, only two trials have been successful in achieving
their primary endpoints over the past two decades. For instance, clinical trials evaluating the merit of adding
[49]
lenalidomide to R-CHOP backbone(E1412 and ROBUST) [24,50] as well as ibrutinib (PHOENIX) , all seemed
like promising interventions, but only one (E1412) of the three trials successfully demonstrated an
[50]
improvement in PFS . Although there is a multitude of reasons why these trials differ in the outcome,
leading thoughts include different methods and approaches to identifying ABC/non-GC DLBCL patients,
the longer interval from the time of diagnosis to initiation of treatment in the ROBUST study compared to
E1412, and lastly, differing dosing of lenalidomide in ROBUST vs. E1412. It is not until recently, with the
addition of a novel antibody-drug conjugate against CD79, polatuzumab-vedotin, to the R-CHOP
[51]
backbone , that we have observed an improvement in the first-line setting in a large randomized, phase III
clinical trial setting. Other attempts to improve upon the R-CHOP backbone are currently on-going
including the addition of other monoclonal antibodies, such as tafasitamab and bispecific antibodies, all of
which can be applied irrespective to COO, similar to polatuzumab-vedotin, thus circumventing the pre-
requisite need to identify DLBCL genetic subgroups prior to enrollment/treatment.

For those who relapse, the standard of care remains chemoimmunotherapy salvage therapy followed by
consolidation with autologous stem cell transplant (ASCT) [52,53] , at least for those who are deemed clinically
fit. However, given that DLBCL is often a disease of the elderly, ASCT may not be a feasible option, leaving
a clear unmet need for these patients. The more recent approvals in CAR-T cellular therapy seem
promising [54-57] , especially for patients who are chemo-refractory to R-CHOP and/or salvage chemotherapy;
however, it is clear that the majority of patients will relapse after CAR-T cell therapy. In the following
section, we will discuss recently FDA-approved agents and their applicability to the treatment paradigm of
DLBCL as well as novel agents in the pipeline that leverage our understanding of the various oncogenic
drivers elucidated by the recent molecular classifications [Figure 1], [Table 2]. For discussion purposes, we
have organized the following section based on COO, rather than the new classification systems, and
highlight some potential agents that can target high-risk subgroups as delineated by LymphGen and cluster
taxonomies.

Targeting specific molecular drivers
Novel agents for the treatment of ABC-DLBCL
ABC-DLBCLs are characterized by the overactivation of B-cell receptor (BCR) and NFκB pathways. Loss of
function mutations/homozygous deletions in A20 [58,59] , and gain of function mutations in CARD11 [58,60] ,
CD79 A/B , MYD88 , as well as the role of CARD11-BCL1-MALT1 complex [63-65] , have all been
[61]
[62]
implicated as drivers of the NFB pathway in ABC-DLBCLs, and attempts to target these pathological drivers
have been made in the past several years. Based on the new molecular classifications, BCR-dependent NFκB
signaling is prevalent in the MCD, A53, and BN2 subtypes, with MCD DLBCLs having an intermediate-
poor prognosis after standard of care .
[4]

One of the first approaches of targeting NFB in ABC-DLBCL was the interrogation of proteasome
inhibitors, such as bortezomib. Although thought to have pleotrophic effects, bortezomib and other
proteasome inhibitors have been used to downregulate NFB activity via inhibition of IB degradation.
However, two frontline studies comparing the addition of bortezomib to R-CHOP vs. R-CHOP in ABC-
DLBCL patients failed to reach their primary endpoints of improved PFS [47,48] .

Another more selective approach to target the ABC-subtype is the inhibition of the Bruton tyrosine kinase
(BTK), which is an essential member of the BCR pathway. Ibrutinib, a first-in-class covalent inhibitor of